Medical devices for delivering a therapeutic agent and method of preparation

ABSTRACT

A method for making an intravascular stent by applying to the body of a stent a solution which includes a solvent, a polymer dissolved in the solvent and a therapeutic substance dispersed in the solvent and then evaporating the solvent. The inclusion of a polymer in intimate contact with a drug on the stent allows the drug to be retained on the stent during expansion of the stent and also controls the administration of drug following implantation. The adhesion of the coating and the rate at which the drug is delivered can be controlled by the selection of an appropriate bioabsorbable or biostable polymer and the ratio of drug to polymer in the solution. By this method, drugs such as dexamethasone can be applied to a stent, retained on a stent during expansion of the stent and elute at a controlled rate.

RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.11/292,171, filed Nov. 30, 2005, which is a Continuation of U.S.application Ser. No. 10/147,872, filed May 20, 2002, now U.S. Pat. No.6,997,949, which is a Continuation of U.S. application Ser. No.09/070,192, filed Apr. 30, 1998, now abandoned, which is aContinuation-in-Part of Ser. No. 08/728,541, filed Oct. 9, 1996, nowU.S. Pat. No. 5,776,184, which is a Divisional of U.S. application Ser.No. 08/482,346, filed Jun. 7, 1995, now U.S. Pat. No. 5,679,400, whichis a Continuation-in-Part of U.S. application Ser. No. 08/052,878, filedApr. 26, 1993, now U.S. Pat. No. 5,464,650, the disclosures of which areall incorporated herein, in their entirety, by reference thereto.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to a medical device employing a therapeutic agentas a component thereof. For example, in an arterial site treated withpercutaneous transluminal coronary angioplasty therapy for obstructivecoronary artery disease a therapeutic antithrombogenic substance such asheparin may be included with a device and delivered locally in thecoronary artery. Also provided is a method for making a medical devicecapable of localized application of therapeutic agents.

Medical devices which serve as substitute blood vessels, synthetic andintraocular lenses, electrodes, catheters, and the like, in and on thebody, or as extracorporeal devices intended to be connected to the bodyto assist in surgery or dialysis are well known. For example,intravascular procedures can bring medical devices into contact with thepatient's vasculature. In treating a narrowing or constriction of a ductor canal percutaneous transluminal coronary angioplasty (PTCA) is oftenused with the insertion and inflation of a balloon catheter into astenotic vessel. Other intravascular invasive therapies includeatherectomy (mechanical systems to remove plaque residing inside anartery), laser ablative therapy, and the like. However, this use ofmechanical repairs can have adverse consequences for the patient. Forexample, restenosis at the site of a prior invasive coronary arterydisease therapy can occur. Although angioplasty procedures haveincreased greatly in popularity for treatment of occluded arteries, theproblem of restenosis following the angioplasty treatment remains asignificant problem. Restenosis is the closure of a peripheral orcoronary artery following trauma to the artery caused by efforts to openan occluded portion of the artery by angioplasty, such as, for example,by balloon dilation, atherectomy or laser ablation treatment of theartery. For these angioplasty procedures, restenosis occurs at a rate ofabout 30-60% depending upon the vessel location, lesion length and anumber of other variables. Restenosis, defined angiographically, is therecurrence of a 50% or greater narrowing of a luminal diameter at thesite of a prior coronary artery disease therapy, such as a balloondilatation in the case of PTCA therapy. In particular, an intra-luminalcomponent of restenosis develops near the end of the healing processinitiated by vascular injury, which then contributes to the narrowing ofthe luminal diameter. This phenomenon is sometimes referred to as“intimal hyperplasia.” It is believed that a variety of biologic factorsare involved in restenosis, such as the extent of the injury, platelets,inflammatory cells, growth factors, cytokines, endothelial cells, smoothmuscle cells, and extracellular matrix production, to name a few.

Attempts to inhibit or diminish restenosis often include additionalinterventions such as the use of intravascular stents and theintravascular administration of pharmacological therapeutic agents. Oneaspect of restenosis may be simply mechanical; e.g. caused by theelastic rebound of the arterial wall and/or by dissections in the vesselwall caused by the angioplasty procedure. These mechanical problems havebeen successfully addressed by the use of stents to tack-up dissectionsand prevent elastic rebound of the vessel, thereby reducing the level ofrestenosis for many patients. The stent is typically inserted bycatheter into a vascular lumen and expanded into contact with thediseased portion of the arterial wall, thereby providing internalsupport for the lumen. Examples of stents which have been successfullyapplied over a PTCA balloon and radially expanded at the same time asthe balloon expansion of an affected artery include the stents disclosedin U.S. Pat. Nos. 4,733,665 (Palmaz), 4,800,882 (Gianturco), and4,886,062 (Wiktor).

Also, such stents employing therapeutic agents such as glucocorticoids(e.g. dexamethasone, beclamethasone), heparin, hirudin, tocopherol,angiopeptin, aspirin, ACE inhibitors, growth factors, oligonucleotides,and, more generally, antiplatelet agents, anticoagulant agents,antimitotic agents, antioxidants, antimetabolite agents, andanti-inflammatory agents have been considered for their potential tosolve the problem of restenosis. Such substances have been incorporatedinto (or onto) stents by a variety of mechanisms. These mechanismsinvolve incorporating the therapeutic agents into polymeric coatings andfilms, including hydrogels, as well as covalently binding thetherapeutic agents to the surface of the stent.

For example, therapeutic agents have been dissolved or dispersed in asolution of polymer in an organic solvent. This is then sprayed onto thestent and allowed to dry. Alternatively, therapeutic agents have beenincorporated into a solid composite with a polymer in an adherent layeron a stent body with fibrin in a separate adherent layer on thecomposite to form a two layer system. The fibrin is optionallyincorporated into a porous polymer layer in this two layer system. Thetherapeutic agent, however, is incorporated into the underlying solidpolymer. The overlying porous polymer layer provides a porous barrierthrough which the therapeutic agent is transferred.

Conventional methods of loading the therapeutic agent into a polymer,such as spray coating, do not provide high concentrations of therapeuticagents. Typically, upon spray coating a therapeutic agent onto a stentbody, only about 2 percent of the spray is captured by the stent. Thiscan be prohibitively expensive for therapeutic agents that are extremelycostly and scarce, such as peptidic drugs.

Thus, what is needed is a medical device, preferably, a stent, having aporous polymeric material, typically a polymer layer in the form of acoating or film, with a therapeutic agent incorporated therein atsufficiently high concentrations that the therapeutic agent can bedelivered over an extended period of time. Improved methods by which thetherapeutic agent can be incorporated into the porous polymeric materialwith lower levels of waste are also needed.

This invention also relates to intravascular stents for treatment ofinjuries to blood vessels and particularly to stents having a frameworkonto which a therapeutic substance or drug is applied.

Metal stents such as those disclosed in U.S. Pat. No. 4,733,665 issuedto Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco or U.S. Pat. No.4,886,062 issued to Wiktor could be suitable for drug delivery in thatthey are capable of maintaining intimate contact between a substanceapplied to the outer surface of the stent and the tissues of the vesselto be treated. However, there are significant problems to be overcome inorder to secure a therapeutically significant amount of a substance ontothe metal of the stent; to keep it on the stent during expansion of thestent into contact with the blood vessel wall; and also controlling therate of drug delivery from the drug on the stent to the vessel wall.

It is therefore another object of the present invention to provide astent having a therapeutically significant amount of a drug appliedthereto.

It is also an object of the present invention to provide a stent whichmay be delivered and expanded in a selected blood vessel without losinga therapeutically significant amount of a drug applied thereto.

It is also an object of the present invention to provide adrug-containing stent which allows for a sustained release of the drugto vascular tissue.

It is also an object of the present invention to provide a simple methodfor applying to a stent a coating of a therapeutic substance.

SUMMARY OF THE INVENTION

This invention relates to a medical device having a porous polymericmaterial with a therapeutic agent therein. Preferably, the deviceaccording to the invention is capable of applying a highly localizedtherapeutic agent into a body lumen to treat or prevent injury. The term“injury” means a trauma, that may be incidental to surgery or othertreatment methods including deployment of a stent, or a biologicdisease, such as an immune response or cell proliferation caused by theadministration of growth factors. In addition, the methods of theinvention may be performed in anticipation of “injury” as aprophylactic. A prophylactic treatment is one that is provided inadvance of any symptom of injury in order to prevent injury, preventprogression of injury or attenuate any subsequent onset of a symptom ofsuch injury.

In accordance with the invention, a device for delivery of localizedtherapeutic agent includes a structure including a porous material andan elutable (i.e., capable of being dissolved under physiologicalconditions) therapeutic agent in the form of a solid, gel, or neatliquid, which is dispersed throughout at least a portion, and preferablya substantial portion, of the porous material. Preferably, the device iscapable of being implanted in a body so that the localized therapeuticagent can be delivered in vivo, typically at a site of vascular injuryor trauma. Preferably, the porous material is biocompatible,sufficiently tear-resistant, and nonthrombogenic.

The porous material may be a layer (e.g., a film, i.e., a sheet materialor a coating) on at least a portion of the structure. Alternatively, theporous material may be an integral portion of the structure. Preferably,the porous material is a polymeric material selected from the group of anatural hydrogel, a synthetic hydrogel, silicone, polyurethane,polysulfone, cellulose, polyethylene, polypropylene, polyamide,polyester, polytetrafluoroethylene, and a combination of two or more ofthese materials. Examples of natural hydrogels include fibrin, collagen,elastin, and the like. More preferably, the porous polymeric material isa nonswelling biostable polymer selected from the group of silicone,polyurethane, polysulfone, cellulose, polyethylene, polypropylene,polyamide, polyester, polytetrafluoroethylene, and a combination of twoor more of these materials.

The therapeutic agent can be one or more of a wide variety oftherapeutic agents, including peptidic drugs. Preferably, thetherapeutic agent includes an antithrombotic material. More preferably,the antithrombotic material is a heparin or heparin derivative oranalog. Such therapeutic agents are soluble in water such that theyelute from the porous polymeric material.

The structure of the device can be adapted for its intendedextracorporeal or intravascular purpose in an internal human body site,such as an artery, vein, urethra, other body lumens, cavities, and thelike or in an extracorporeal blood pump, blood filter, blood oxygenatoror tubing. In one aspect of the invention, the shape is preferablygenerally cylindrical, and more preferably, the shape is that of acatheter, a stent, or a guide wire. In particularly preferredembodiments, the medical device is an intralumenal stent.

The invention also provides methods for making a medical device whichincludes therapeutic agents. In one embodiment, a method of theinvention includes: providing a structure comprising a porous material;contacting the structure comprising a porous material with aconcentrating agent to disperse the concentrating agent throughout atleast a portion of the porous material; contacting the structurecomprising a porous material and the concentrating agent with a solutionof a therapeutic agent; and removing the therapeutic agent from solutionwithin the porous material at the locations of the concentrating agent.

The present invention also provides a method for making a medical devicethat includes: providing a structure comprising a porous material;immersing the structure comprising a porous material in a saturatedsolution of a therapeutic agent for a sufficient period of time to allowthe solution to fill the porous material; removing the medical devicefrom the solution; drying the medical device; and repeating the steps ofimmersing, removing, and drying to provide a therapeutic agent dispersedwithin the porous material. Preferably, the method further includes astep of removing air bubbles from the porous material while beingimmersed in the solution of the therapeutic agent. The step of removingair bubbles from the porous material can include applying ultrasonics,reduced pressure, elevated pressure, or a combination thereof, to thesolution. Preferably, the method involves loading a stent having aporous polymeric film thereon, and subsequently applying an overlayer ofa polymer.

A therapeutic agent may be loaded onto a structure including a porousmaterial at any number of points between, and including, the point ofmanufacture and the point of use. For example, the device can be storedand transported prior to incorporation of the therapeutic agent. Thus,the end user can select the therapeutic agent to be used from a widerrange of therapeutic agents.

We have discovered a method for making an intravascular stent byapplying to the body of a stent, and in particular to itstissue-contacting surface, a solution which includes a solvent, apolymer dissolved in the solvent and a therapeutic substance dispersedin the solvent and then evaporating the solvent. The inclusion of apolymer in intimate contact with a drug on the stent allows the drug tobe retained on the stent in a resilient matrix during expansion of thestent and also slows the administration of drug following implantation.The method can be applied whether the stent has a metallic or polymericsurface. The method is also an extremely simple method since it can beapplied by simply immersing the stent into the solution or by sprayingthe solution onto the stent. The amount of drug to be included on thestent can be readily controlled by applying multiple thin coats of thesolution while allowing it to dry between coats. The overall coatingshould be thin enough so that it will not significantly increase theprofile of the stent for intravascular delivery by catheter. It istherefore preferably less than about 0.002 inch thick and mostpreferably less than 0.001 inch thick. The adhesion of the coating andthe rate at which the drug is delivered can be controlled by theselection of an appropriate bioabsorbable or biostable polymer and bythe ratio of drug to polymer in the solution. By this method, drugs suchas glucocorticoids (e.g. dexamethasone, betamethasone), heparin,hirudin, tocopherol, angiopeptin, aspirin, ACE inhibitors, growthfactors, oligonucleotides, and, more generally, antiplatelet agents,anticoagulant agents, antimitotic agents, antioxidants, antimetaboliteagents, and anti-inflammatory agents can be applied to a stent, retainedon a stent during expansion of the stent and elute the drug at acontrolled rate. The release rate can be further controlled by varyingthe ratio of drug to polymer in the multiple layers. For example, ahigher drug-to-polymer ratio in the outer layers than in the innerlayers would result in a higher early dose which would decrease overtime.

In operation, the stent made according to the present invention candeliver drugs to a body lumen by introducing the stent transluminallyinto a selected portion of the body lumen and radially expanding thestent into contact with the body lumen. The transluminal delivery can beaccomplished by a catheter designed for the delivery of stents and theradial expansion can be accomplished by balloon expansion of the stent,by self-expansion of the stent, or a combination of self-expansion andballoon expansion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an elevational view of one embodiment of a device according tothe invention with a balloon catheter as a mode of delivery of thedevice; and

FIG. 2 is an elevational view of another embodiment of a deviceaccording to the invention with a balloon catheter as a mode of deliveryof the device.

FIG. 3 is a plot showing elution profiles for stents according to thepresent invention with a coating of dexamethasone and poly(L-lacticacid) made according to Example 7.

FIG. 4 is a plot showing elution profiles for sterilized stentsaccording to the present invention with a coating of dexamethasone andpoly(L-lactic acid) made according to Example 8.

DESCRIPTION OF PREFERRED EMBODIMENTS

One of the more preferred configurations for a device according to theinvention is a stent for use in artery/vascular therapies. The term“stent” refers to any device capable of being delivered by a catheterand which, when placed into contact with a portion of a wall of a lumento be treated, will also deliver localized therapeutic agent at aluminal or blood-contacting portion of the device. A stent typicallyincludes a lumen wall-contacting surface and a lumen-exposed surface.Where the stent is shaped generally cylindrical or tube-like, includinga discontinuous tube or ring-like structure, the lumen-wall contactingsurface is the surface in close proximity to the lumen wall whereas thelumen-exposed surface is the inner surface of the cylindrical stent. Thestent can include polymeric or metallic elements, or combinationsthereof, onto which a porous material is applied. For example, adeformable metal wire stent is useful as a stent framework of thisinvention, such as that described in U.S. Pat. No. 4,886,062 (Wiktor),which discloses preferred methods for making a wire stent. Othermetallic stents useful in this invention include those of U.S. Pat. Nos.4,733,655 (Palmaz) and 4,800,882 (Gianturco).

Other medical devices, such as heart valves, vascular grafts, pacingleads, etc., can also include the embodiments of the present invention.As used herein, medical device refers to a device that has surfaces thatcontact tissue, blood, or other bodily fluids in the course of theiroperation, which fluids are subsequently used in patients. This caninclude, for example, extracorporeal devices for use in surgery such asblood oxygenators, blood pumps, blood sensors, tubing used to carryblood and the like which contact blood which is then returned to thepatient. This can also include endoprostheses implanted in blood contactin a human or animal body such as vascular grafts, stents, pacemakerleads, heart valves, and the like that are implanted in blood vessels orin the heart. This can also include devices for temporary intravascularuse such as catheters, guide wires, and the like which are placed intothe blood vessels or the heart for purposes of monitoring or repair.

Referring now to FIG. 1, the stent 20 comprises a stent framework 22 anda porous material coating 24. The stent framework 22 is deformable andcan be formed from a polymeric material, a metal, or a combinationthereof. A balloon 15 is positioned in FIG. 1 adjacent the lumen-exposedsurface of the stent to facilitate delivery of the stent. The stent 20can be modified to increase or to decrease the number of wires providedper centimeter in the stent framework 22. Similarly, the number of wireturns per centimeter can also be modified to produce a stiffer or a moreflexible stent framework.

Polymeric stents can also be used in this invention. The polymers can benonbioabsorbable or bioabsorbable in part, or total. Stents of thisinvention can be completely nonbioabsorbable, totally bioabsorbable or acomposite of bioabsorbable polymer and nonabsorbable metal or polymer.For example, another stent suitable for this invention includes theself-expanding stent of resilient polymeric material as disclosed inInternational Publication No. WO 91/12779 (Medtronic, Inc.).

Nonbioabsorbable polymers can be used as alternatives to metallicstents. The stents of this invention should not substantially induceinflammatory and neointimal responses. Examples of biostablenonabsorbable polymers that have been used for stent construction withor without metallic elements include polyethylene terephthalate (PET),polyurethane urea, and silicone. Although the porous material is shownas a coating 24, it is to be understood that, for the purposes of thisinvention, the porous material can be incorporated into the material ofthe stent.

Referring to FIG. 2, an alternative stent 30 is shown. The stentframework 34 is affixed with a film of a porous material 32. This can beaccomplished by wrapping the film 32 around the stent framework 34 andsecuring the film 32 to the framework 34 (i.e., the film is usuallysufficiently tacky to adhere itself to the framework but a medical gradeadhesive could also be used if needed) so that the film 32 will stay onthe balloon 36 and framework 34 until it is delivered to the site oftreatment. The film 32 is preferably wrapped over the framework withfolds or wrinkles that will allow the stent 30 to be readily expandedinto contact with the wall of the lumen to be treated. Alternatively,the film 32 can be molded to the stent framework 34 such that theframework 34 is embedded within the film 32. Preferably, the film 32 islocated on a lumen-wall contacting surface 33 of the stent framework 34such that therapeutic material is substantially locally delivered to alumen wall, for example, an arterial wall membrane (not shown).

Porous Material

As mentioned above, the device according to the invention is generally astructure including a porous material. In one embodiment, the porousmaterial includes a polymeric film or coating on at least a portion ofthe structure. In another embodiment, the porous material is an integralportion of the structure. Preferably, the porous material is abiocompatible polymer and is sufficiently tear-resistant andnonthrombogenic. Examples of suitable polymers are disclosed in U.S.Pat. No. 5,679,400 (Tuch). More preferably, the porous material isselected from the group of a natural hydrogel, a synthetic hydrogel,silicone, polyurethane, polysulfone, cellulose, polyethylene,polypropylene, polyamide, polyester, polytetrafluoroethylene, and acombination of two or more of these materials. Examples of naturalhydrogels include fibrin, collagen, elastin, and the like. In materialswhich do not include pores in their usual structural configurations,pores of about 10 micrometers in diameter or as large as 1000micrometers in diameter can be introduced by conventional means such asby introducing a solvent soluble particulate material into the desiredstructure and dissolving the particulate material with a solvent.

Typically, and preferably, the porous material is in the form of a sheetmaterial or coating of a nonswelling biostable polymer. As used herein,a “nonswelling biostable” or “nonswellable biostable” polymer is onethat does not absorb a significant amount of water (i.e., it absorbsless than about 10 weight percent water) and it is not readily degradedin the body. Such nonswelling biostable polymers include, for example,silicone, polyurethane, polysulfone, cellulose, polyethylene,polypropylene, polyamide, polyester, polytetrafluoroethylene, andcombinations thereof. If the polymer is biodegradable, the rate at whichit degrades is slower than the rate at which the therapeutic agentelutes.

If the porous material is in the form of a porous sheet (i.e., film) orcoating, it can be made by a variety of methods. These methods caninclude, for example, using a solid particulate material (also referredto herein as pore-forming material) that can be substantially removedafter the film or coating is formed, thereby forming pores. By using asolid particulate material during film or coating formation, the size ofthe pores can, to some extent, be controlled by the size of the solidparticulate material being used. The particulate material can range fromless than about 1 micrometer in diameter to about 1000 micrometers,preferably about 1 micrometer to about 100 micrometers, more preferablyabout 5 micrometers to about 50 micrometers. For uniformity of pores,the particulate material can be screened through successively finer meshsieves, e.g., through 100, 170, 270, 325, 400, and 500 mesh analyticalgrade stainless steel mesh sieves, to produce a desired range ofparticle sizes.

The particulate material may include inorganic and organic particulatematerial, including, for example, sodium chloride, lithium chloride,sucrose, glucose, sorbitol, sodium citrate, sodium ascorbate, urea,citric acid, dextran, poly(ethylene glycol), sodium nitroprusside,mannitol, sodium bicarbonate, ascorbic acid, sodium salicylate, orcombinations thereof. It will be understood by one of skill in the artthat a mixture of different particulate materials can be used ifdesired. Also, it will be understood by one of skill in the art thatbecause a portion of the particulate material may remain within thefilm, it is preferred that the solid particulate material bebiocompatible.

Typically, the particulate material chosen is less soluble than thepolymer in the chosen solvent (e.g., water or an organic solvent) usedto deposit or form the polymer. The particulate material may actually besoluble in the solvent; however, to form pores, it only has to be lesssoluble than the polymer in the solvent of choice. As the solvent isremoved from the solution, the pore-forming material will precipitateout of solution and form particles surrounded by the polymer, which isstill in solution. The polymer then will come out of solution as moresolvent is removed and the particles will be dispersed within thepolymer. After the solvent is removed, the particulate material isremoved using a liquid in which the polymer is not soluble, therebyforming pores.

In one method according to the present invention, a porous sheetmaterial (e.g., polyurethane sheet material) can be made by dissolving apolymer (e.g., polyether urethane) in an organic solvent (e.g.,1-methyl-′2-pyrrolidone); mixing into the resulting polymer solution acrystalline, particulate material (e.g., sodium chloride, sucrose, etc.)that is not soluble in the solvent; casting the solution withparticulate material into a thin film; and then applying a secondsolvent (e.g., water), to dissolve and remove the particulate material,thereby leaving a porous sheet. Such a method is disclosed in U.S. Pat.Nos. 5,591,227 (Dinh et al.) and 5,599,352 (Dinh et al.).

Preferably, a combination of soluble and insoluble particulate materialmay be used to create a broader range of pore sizes. The use of asoluble particulate material, such as poly(ethylene glycol), may createsmall (<2 μm diameter) interconnecting pores that create a solvent pathfor the removal of the larger (e.g., 50 μm) particles, which may not bein particle-to-particle contact.

A suspension of particulate material may be created by first dissolvingthe particulate in a solvent, then precipitating the mixture in asolution of polymer in a second solvent in which the particulate isinsoluble. For example, an 8% solution of sodium nitroprusside inethanol can be added with rapid stirring to a 2% solution ofpolyurethane in tetrahydrofuran. The sodium nitroprusside precipitatesto form a suspension of less than about 5 μm particles.

The weight ratio of pore-forming material to polymer in a coatingcomposition may range from about 1:3 to about 9:1, preferably, about 2:1to about 9:1, although this is not necessarily limiting. In theory, theporosity is limited by the toughness of the polymer.

A smooth coating may be obtained by applying an atomized spray to thestent. The spray should be applied at a rate such that evaporationprevents the accumulation of sufficient liquid to form drips along thestent. A macroscopically smooth surface may also be obtained by keepingthe particle size less than about ′A of the coating or film thickness.

Although films (i.e., sheet materials) for medical devices, particularlystent bodies, according to the present invention can be manufacturedseparately from the support structure of the medical device and attachedto the support structure after formation, preferred methods includeforming the films directly on the support structure such that thesupport structure is at least partially, preferably completely,encapsulated by the film (i.e., sheet material).

Alternatively, medical devices can include a coating of a porous polymermade by spraying a solution of the polymer and particulate materialdirectly on the support. In this way, the coating does not necessarilyform a film that encapsulates the device; rather it forms a coatingaround the structure (e.g., wire) of the device. The geometry of theporous material (coated wires vs. sheets or films) depends on thecoating substrate and is largely independent of the pore forming andapplication methods used. A film can be made by spraying, dipping, orcasting, as long as the mandrel is a rod or a flat sheet. The stentwires can be coated by any of these methods as well, although mostpreferably, they are coated by spraying to prevent droplet formation.

In one such method, which is disclosed in International Publication No.WO 97/07973 (Medtronic, Inc.), a stent is placed on a mandrel. Aparticulate material is then applied to the mandrel and stent such thatit is lightly adhered to the mandrel. The particulate material should bereadily soluble in a solvent which will not also dissolve the polymerchosen for the film. For example, crystalline sodium bicarbonate is awater soluble material that can be used as the particulate material. Anonaqueous liquid, preferably a solvent for the polymer film material,can be applied to the mandrel before applying the particulate materialin order to retain more of the particulate material on the mandrel. Forexample, when a polyurethane is to be used for the film material, thesolvent 1-methyl-2-pyrrolidinone (NMP) can be used to wet the surface ofthe mandrel before the application of particulate material. Preferably,the mandrel is completely dusted with the particulate in the portions ofthe mandrel to be coated with the polymer film. This can be accomplishedby dipping the mandrel in NMP, allowing it to drain vertically for a fewseconds and then dusting the sodium bicarbonate onto the mandrel whilerotating it horizontally until no further bicarbonate particles adhere.Excess particulate material can be removed by gently tapping themandrel.

Coating with polymer may proceed immediately following application ofthe particulate material. A polymer is provided in a dilute solution andis applied to the particle-coated stent and mandrel. For example,polyurethane can be dissolved in NMP to make a 10% solution. Gelparticles and particulate impurities can be removed from the solution byuse of a clinical centrifuge. The polymer solution can be applied bydipping the mandrel into the solution and letting the solvent evaporate.With the solution of polyurethane and NMP, a single dip in the solutioncan provide a film of adequate thickness. To assist in the formation ofcommunicating passageways through the polymer between theblood-contacting surface and the lumen-contacting surface, additionalsodium bicarbonate particles are preferably dusted onto the polymersolution immediately after the dipping operation and before the polymersolution has dried. Excess particulate material can be removed by gentlytapping the mandrel. To precipitate and consolidate the polyurethanefilm on the stent, it can be dipped briefly (about 5 minutes) in waterand then rolled gently against a wetted surface, such as a wet papertowel. The stent assembly can then be placed into one or more waterbaths over an extended period (e.g., 8 hours) to dissolve and remove thesodium bicarbonate. After drying in air at temperatures from about 20°C. to about 50° C., the film then can be trimmed to match the contour ofthe wire.

In yet another method, a solvent in which the polymer is soluble that iscapable of phase separating from the polymer at a reduced temperaturecan be used to prepare a porous polymer film. In this method, the stentor other medical device is placed in a cavity of a mold designed forforming a film around the stent, similar to that disclosed in U.S. Pat.No. 5,510,077 (Dinh et al.). A solution of the desired polymer, such aspolyurethane, dissolved in a solvent, such as dioxane, is added to themold. The temperature of the solution is then reduced to a temperatureat which the solvent freezes and phase separates from the polymer,thereby forming particulate material (i.e., frozen solvent particles) insitu. Typically, for polyurethane in dioxane, this is a temperature ofabout −70° C. to about 3° C. The composition is then immersed in an icecold water bath (at about 3° C.) for a few days to allot the dioxane todissolve into the ice cold water, thereby forming pores. The number andsize of the pores can be controlled by the concentration of the polymerand the freezing temperature. A method similar to this is disclosed inLiu et al., J. Biomed. Mater. Res., 26, 1489 (1992). This method can beimproved on by using a two-step freezing process as disclosed in U.S.patent application Ser. No., filed on Apr. 29, 1998 (09/069659).

In yet another embodiment, a porous material can be created from amixture of a low boiling good solvent and a higher boiling poor solvent,in which the polymer is soluble. After application to the targetsubstrate, the lower boiling good solvent evaporates preferentiallyuntil a point is reached where the polymer precipitates from theremaining solvent mixture, which is relatively richer in the poorsolvent. The polymer precipitates in and around pockets of the poorsolvent, creating a porous structure. The number and size of pores canbe controlled by the boiling points of the two solvents, theconcentration of polymer and the drying rate. An example is a 1%solution of poly(1-lactic acid) (PLLA) in a 60:40 mixture ofchloroform:iso-octane. As the chloroform evaporates, the PLLAprecipitates from the iso-octane to create an opaque PLLA coatingcontaining 2-5 μm pores. This method is further described in U.S. Pat.No. 5,679,400 (Tuch).

Therapeutic Agent

The therapeutic agent used in the present invention could be virtuallyany therapeutic agent which possesses desirable therapeuticcharacteristics and which can be provided in a form that can besolubilized, for example, by water or an organic solvent, and arecapable of being eluted from the porous polymeric material in the bodyof a patient. Preferred therapeutic agents are solids, gels, or neatliquids (i.e., materials not dissolved in a solvent) at room temperature(i.e., about 20-25° C.), and preferably at body temperatures, that arecapable of being eluted from the porous polymeric material in the bodyof a patient. For example, antithrombotics, antiplatelet agents,antimitotic agents, antioxidants, antimetabolite agents,anti-inflammatory agents, enzyme inhibitors, and anti-angiogenic factorsas disclosed in U.S. Pat. No. 5,716,981 (Hunter et al.) could be used.Anticoagulant agents, such as heparin, heparin derivatives, and heparinanalogs, could also be used to prevent the formation of blood clots onthe device.

Methods of Making an Implantable Device

A structure having a porous material, preferably a porous polymericmaterial, can be loaded with one or more therapeutic agents using a widevariety of methods. For example, the porous material can be immersed ina solution or dispersion of the therapeutic agent in a solvent. Thesolution (preferably, a supersaturated solution) or dispersion isallowed to fill the pores and the solvent is allowed to evaporateleaving the therapeutic agent dispersed within at least a portion of thepores. The solvent can be water or an organic solvent that does notdissolve the polymer. If the solvent does not dissolve the therapeuticagent, the particles of the therapeutic agent are smaller than the poreopenings. Alternatively, in certain embodiments, the solvent can bechosen such that it swells the polymer, thereby achieving a greaterlevel of incorporation of the therapeutic agent.

The following methods for loading one or more therapeutic agents intoporous material are improved over prior art methods, such as spraycoating methods. Although the same amount of therapeutic agent can beloaded onto a medical device, significantly less (e.g., about 100× less)waste of the therapeutic agent occurs using the following methods. Thisis particularly important for expensive therapeutic agents, such aspeptic drugs.

In one embodiment of the invention, filling of the pores can be enhancedthrough the use of ultrasonics, vacuum, and/or pressure. While thedevice is submerged in solution, ultrasonic energy or vacuum can be usedto accelerate the removal of air bubbles from the pores allowing thepores to fill with the solution containing the therapeutic agent.Hyperbaric pressure on the solution may cause the air in the pores to bedissolved in the solution, thereby allowing the pores to fill withliquid. Furthermore, the level of incorporation can be increased byusing multiple dip-vacuum-dry cycles. If the therapeutic agent saturatesthe solution by 10% by volume, for example, when the solvent evaporatesthe pores will be 10% filled with the agent. Repeating the cycle willfill the remaining 90% void space and fill an additional 9% of theoriginal pore volume. Further cycles continue the trend. For thisprocedure to be effective, however, the solution is saturated so thatthe previously deposited agent does not dissolve in subsequent cycles.

Preferably, a method of the invention includes loading a structurecomprising a porous material with a concentrating agent, which may be aprecipitating agent (e.g., a binding agent, sequestering agent,nucleating agent, etc.), a seed crystal, or the like, dispersedthroughout at least a portion, preferably, a substantial portion, of theporous material, and subsequently loading the structure comprising aporous material and the concentrating agent with a solution of atherapeutic agent, wherein the therapeutic agent is removed fromsolution (e.g., as by crystallization and/or precipitation) within theporous material at the locations of the concentrating agent. This is asignificantly improved method in that the concentrating agent provides adriving force for localization of the drug within the pores of thepolymer. That is, it is believed that the concentrating agent provides athermodynamically favorable surface for crystallization orprecipitation.

The concentrating agent can be a precipitating agent or a seed crystal,for example, or any substance that can cause the therapeutic agent tofall out of solution. As used herein, a seed crystal is a solid materialthat is the same as the therapeutic agent being deposited. As usedherein, a precipitating agent is a solid material that is different fromthe therapeutic agent being deposited. It can include, for example,materials that have a particular affinity for the therapeutic agent ofinterest, such as binding agents, sequestering agents, nucleatingagents, and mixtures thereof. Examples of sequestering agents includeheparin to sequester heparin binding growth factors such as bFGF and,for example, cyclodextrins to trap appropriately sized therapeuticagents to fit in their ring structures. Examples of binding agentsinclude polycations (e.g., protamine) and polyanions (e.g., heparinsulfate) for binding anionic and cationic therapeutic agents,respectively. The binding agent can also include a counterion of a saltthat is insoluble upon complexation with the therapeutic agent in thesolvent used in the solution of the therapeutic agent.

The solution containing the therapeutic agent is preferably asupersaturated solution, although this is not a necessary requirement.This can be prepared at elevated temperatures taking into considerationthe limits of stability of the therapeutic agents and the porousmaterial. The porous polymeric material with concentrating agent thereincan be immersed in a solution of the therapeutic agent in a solvent. Thesolution is allowed to fill the pores and the therapeutic agent allowedto come out of solution (e.g., as by the formation of crystals). Thesolvent can be water or an: organic solvent that does not dissolve theporous polymer, although it may swell the polymer as described above.The choice of solvent is one that is compatible with the therapeuticagent and porous material of choice. Filling of the pores can beenhanced through the use of ultrasonics, vacuum, and/or pressure, aswell as by using multiple dip-vacuum-dry cycles, as described above.

Crystal and/or precipitate formation can be initiated by a variety ofmechanisms. They may spontaneously form. Alternatively, the solution ofthe therapeutic agent within the pores may need to be cooled to initiatecrystallization and/or precipitation. It may be possible to initiatecrystallization and/or precipitation by changing the pH and/or ionicstrength of the solution of the therapeutic agent within the pores.

The initial concentrating agent, which may be a solid, liquid, or a gel,can be placed in the pores of the porous material by a variety ofmethods. For example, if the concentrating agent is a seed crystal ofthe therapeutic agent of interest, immersing the porous material in asolution or dispersion of the therapeutic agent in a solvent, allowingit to fill the pores, and allowing the solvent to evaporate, providesthe therapeutic agent dispersed within at least a portion of the pores,as described above. Similarly, if the concentrating agent is aprecipitating agent, the porous material can be immersed in a solutionof this agent.

The methods of the present invention are advantageous in that thestructure can be loaded with the therapeutic agent in situ, i.e., at ornear the point of therapeutic use, typically before administration,preferably implantation, to a patient. This is particularly usefulbecause the device can be stored and transported prior to incorporationof the therapeutic agent. This feature has several advantages. Forexample, the relevant consumer can select the therapeutic agent to beused from a wider range of therapeutic agents. Thus, the therapeuticagent selected is not limited to only those supplied with the device butcan instead be applied according to the therapy required.

In order to provide additional control over the elution of thetherapeutic agent, an overlayer may be applied to the medical device, asis disclosed in U.S. Pat. Nos. 5,679,400 (Tuch), 5,624,411 (Tuch), and5,624,411 (Tuch). The overlayer, typically in the form of a porouspolymer, is in intimate contact with the therapeutic agent and allows itto be retained on the medical device. It also controls theadministration of the therapeutic agent following implantation. For astent, an overlayer is particularly desirable to retain the therapeuticagent on the stent during expansion of the stent. Thus, the presentinvention also relates to a method for making an intravascular stent.The underlying structure of the stent can be virtually any stent design,whether of the self-expanding type or of the balloon-expandable type andwhether metal or polymeric. Thus metal stent designs such as thosedisclosed in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No.4,800,882 issued to Gianturco or U.S. Pat. No. 4,886,062 issued toWiktor could be used in the present invention. The stent could be madeof virtually any bio-compatible material having physical propertiessuitable for the design. For example, tantalum and stainless steel havebeen proven suitable for many such designs and could be used in thepresent invention. Also, stents made with biostable or bioabsorbablepolymers such as poly(ethylene terephthalate), polyacetal, poly(lacticacid), poly(ethylene oxide)/poly(butylene terephthalate) copolymer couldbe used in the present invention. Although the stent surface should beclean and free from contaminants that may be introduced duringmanufacturing, the stent surface requires no particular surfacetreatment in order to retain the coating applied in the presentinvention. Both the inner and outer surfaces of the stent may beprovided with the coating according to the present invention.

In order to provide the coated stent according to the present invention,a solution which includes a solvent, a polymer dissolved in the solventand a therapeutic substance dispersed in the solvent is first prepared.It is important to choose a solvent, a polymer and a therapeuticsubstance that are mutually compatible. It is essential that the solventis capable of placing the polymer into solution at the concentrationdesired in the solution. It is also essential that the solvent andpolymer chosen do not chemically alter the therapeutic character of thetherapeutic substance. However, the therapeutic substance only needs tobe dispersed throughout the solvent so that it may be either in a truesolution with the solvent or dispersed in fine particles in the solvent.Examples of some suitable combinations of polymer, solvent andtherapeutic substance are set forth in Table 1 below.

TABLE 1 THERAPEUTIC POLYMER SOLVENT SUBSTANCE poly(L-lactic acid)chloroform dexamethasone poly(lactic acid-co- acetone dexamethasoneglycolic acid) polyether urethane N-methyl pyrrolidone tocopheral(vitamin E) silicone adhesive xylene dexamethasone phosphatepoly(hydroxy-butyrate- dichloro-methane aspirin co-hydroxyvalerate)fibrin water (buffered saline) heparin

The solution is applied to the stent and the solvent is allowed toevaporate, thereby leaving on the stent surface a coating of the polymerand the therapeutic substance. Typically, the solution can be applied tothe stent by either spraying the solution onto the stent or immersingthe stent in the solution. Whether one chooses application by immersionor application by spraying depends principally on the viscosity andsurface tension of the solution, however, it has been found thatspraying in a fine spray such as that available from an airbrush willprovide a coating with the greatest uniformity and will provide thegreatest control over the amount of coating material to be applied tothe stent. In either a coating applied by spraying or by immersion,multiple application steps are generally desirable to provide improvedcoating uniformity and improved control over the amount of therapeuticsubstance to be applied to the stent.

The polymer chosen must be a polymer that is biocompatible and minimizesirritation to the vessel wall when the stent is implanted. The polymermay be either a biostable or a bioabsorbable polymer depending on thedesired rate of release or the desired degree of polymer stability, buta bioabsorbable polymer is probably more desirable since, unlike abiostable polymer, it will not be present long after implantation tocause any adverse, chronic local response. Bioabsorbable polymers thatcould be used include poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), copoly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid. Also,biostable polymers with a relatively low chronic tissue response such aspolyurethanes, silicones, and polyesters could be used and otherpolymers could also be used if they can be dissolved and cured orpolymerized on the stent such as polyolefins, polyisobutylene andethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinylhalide polymers and copolymers, such as polyvinyl chloride; polyvinylethers, such as polyvinyl methyl ether; polyvinylidene halides, such aspolyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile,polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinylesters, such as polyvinyl acetate; copolymers of vinyl monomers witheach other and olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; polyamides, such as Nylon 66 and polycaprolactam; alkydresins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxyresins, polyurethanes; rayon; rayon-triacetate; cellulose, celluloseacetate, cellulose butyrate; cellulose acetate butyrate; cellophane;cellulose nitrate; cellulose propionate; cellulose ethers; andcarboxymethyl cellulose.

The ratio of therapeutic substance to polymer in the solution willdepend on the efficacy of the polymer in securing the therapeuticsubstance onto the stent and the rate at which the coating is to releasethe therapeutic substance to the tissue of the blood vessel. Morepolymer may be needed if it has relatively poor efficacy in retainingthe therapeutic substance on the stent and more polymer may be needed inorder to provide an elution matrix that limits the elution of a verysoluble therapeutic substance. A wide ratio of therapeutic substance topolymer could therefore be appropriate and could range from about 10:1to about 1:100.

The therapeutic substance used in the present invention could bevirtually any therapeutic substance which possesses desirabletherapeutic characteristics for application to a blood vessel. This caninclude both solid substances and liquid substances. For example,glucocorticoids (e.g. dexamethasone, betamethasone), heparin, hirudin,tocopherol, angiopeptin, aspirin, ACE inhibitors, growth factors,oligonucleotides, and, more generally, antiplatelet agents,anticoagulant agents, antimitotic agents, antioxidants, antimetaboliteagents, and anti-inflammatory agents could be used. Antiplatelet agentscan include drugs such as aspirin and dipyridamole. Aspirin isclassified as an analgesic, antipyretic, anti-inflammatory andantiplatelet drug. Dypridimole is a drug similar to aspirin in that ithas anti-platelet characteristics. Dypridimole is also classified as acoronary vasodilator. Anticoagulant agents can include drugs such asheparin, coumadin, protamine, hirudin and tick anticoagulant protein.Antimitotic agents and antimetabolite agents can include drugs such asmethotrexate, azathioprine, vincristine, vinblastine, fluorouracil,adriamycin and mutamycin.

The following nonlimiting examples will further illustrate theinvention. All parts, percentages, ratios, etc. are by weight unlessotherwise indicated.

EXAMPLES Example 1

Wiktor stents were coated as follows: 4 grams of a 5 wt % solution ofpolyurethane as disclosed in U.S. Pat. No. 4,873,308 (Coury et al.) intetrahydrofuran (THF) and 20 grams of a 5 wt % solution of citric acidin THF were combined and sprayed onto wiktor stents using an air brush,similar to the method disclosed in U.S. Pat. No. 5,679,400 (Tuch).Citric acid was extracted with deionized water for 10 minutes. The stentwas then air dried at ambient temperature and weighed. The porouspolyurethane coating weights, were 0.5-0.7 mg.

Into a microcentrifuge tube was added 0.12 g tissue factor pathwayinhibitor. (TFPI) and 1.0 ml sterile water. This was agitated todissolve the TFPI. The polyurethane coated stents were immersed in theTFPI solution, which was subjected to reduced pressure (28 inches of Hg)to evacuate the air from the pores. The stents were air dried and theimmersion/vacuum process was repeated twice. After the last immersionprocess, stents were air dried at ambient temperature for 20 minutes.Each stent was immersed for less than two seconds in deionized water toremove TFPI on the surface of the stents. The stents were then dried inambient temperature under vacuum for about 12 hours. The stents wereweighed to determine the amount of TFPI loaded into the pores, whichranged from 0.15 mg to 0.33 mg.

Half the stents were overcoated with a 2 wt % solution of polyurethanesolution in THF using the spray coating method described above,resulting in a coating weight of 0.6 mg. These stents were tested forelution. The stents with the overcoating eluted more slowly than thestents without the overcoating.

Example 2

A 1% solution of dexamethasone in acetone was made, forming a clearsolution. The solution was placed in an airbrush reservoir (Badger#200). Wiktor type tantalum wire stents were sprayed with the solutionin short bursts while rotating the stents. The acetone quicklyevaporated from the stents, leaving a white residue on the stent wire.The process was continued until all of the stent wires were coated. Thedrug elution rate for the stent was determined by immersing the stent inphosphate buffered saline solution (pH=7.4). Traces of dexamethasonewere observed to remain on the immersed stents for less than 31 hours.

Example 3

A 2% solution of dexamethasone in acetone was made, forming a solutionwith suspended particles of dexamethasone. The solution was placed intoa tube. Wiktor type tantalum wire stents were dipped rapidly and wereallowed to dry. Each stent was dipped into the solution 12-15 times toprovide a white surface coating. Two stents were placed on anangioplasty balloon and were inflated on the balloon. Approximately 80%of the dexamethasone coating flaked off of the stents.

Example 4

A solution of 1% dexamethasone and 0.5% poly(caprolactone) (Aldrich 18,160-9) in acetone was made. The solution was placed into a tube. Wiktortype tantalum wire stents were dipped rapidly and were allowed to dry.Each stent was dipped into the solution 12-15 times to provide a whitesurface coating. A stent so coated was expanded on a 3.5 mm angioplastyballoon causing a significant amount of the coating to become detached.

Example 5

A solution of 1% dexamethasone and 0.5% poly(L-lactic acid) (Medisorb)in acetone was made. The solution was placed into a tube. Wiktor typetantalum wire stents were dipped rapidly and were allowed to dry. Eachstent was dipped into the solution 12-15 times to provide a whitesurface coating. A stent so coated was expanded on a 3.5 mm angioplastyballoon causing only a small portion of the coating (less than 25%) tobecome detached)

Example 6

A solution including a 2% dispersion of dexamethasone and a 1% solutionof poly(L-lactic acid) (CCA Biochem MW=550,000) in chloroform was made.The solution was placed into an airbrush (Badger). Wiktor type tantalumwire stents were sprayed in short bursts and were allowed to dry. Eachstent was sprayed with the solution about 20 times to provide a whitesurface coating. A stent so coated was expanded on a 3.5 mm angioplastyballoon. The coating remained attached to the stent throughout theprocedure.

Example 7

A solution including a 2% dispersion of dexamethasone and a 1% solutionof poly(L-lactic acid) (CCA Biochem MW=550,000) in chloroform was made.The solution was placed into an airbrush (Badger #250-2). Wiktor typetantalum wire stents were suspended from a fixture and sprayed in 24short bursts (6 bursts from each of the four directions perpendicular tothe stent axis) and were allowed to dry. The resulting stents had acoating weight of about 0.0006-0.0015 grams. Three of the stents weretested for long term elution by placing one stent in 3.0 ml of phosphatebuffered saline solution (pH=7.4) at room temperature without stirring.The amount of dexamethasone eluted was evaluated by measuring absorbanceat 244 nm in a UV-VIS spectrophotometer. The results of this test aregiven in FIG. 3.

Example 8

A solution including a 2% dispersion of dexamethasone and a 1% solutionof poly(L-lactic acid) (Medisorb 100-L) in chloroform was made alongwith a control solution of 1% of poly(L-lactic acid) (Medisorb 100-L) inchloroform. The solutions was placed into an airbrush (Badger #250-2).Wiktor type tantalum wire stents were expanded on a 3.0 mm balloon,suspended from a fixture and sprayed in 16 short bursts (2-3 bursts ofabout 1 second followed by several minutes drying time betweenapplications). The resulting dexamethasone-coated stents had an averagecoating weight of about 0.0012 grams while the polymer-coated stents hadan average polymer weight of about 0.0004 grams. The stents weresterilized in ethylene oxide. Three of the sterilizeddexamethasone-coated stents were tested for long term elution by placingone stent in 3.0 ml of phosphate buffered saline solution (pH=7.4) atroom temperature without stirring. The amount of dexamethasone elutedwas evaluated by measuring absorbance at 244 nm in a UV-VISspectrophotometer. The results of this test are given in FIG. 4.Dexamethasone-coated stents and polymer-coated control stents wereimplanted in the coronary arteries of 8 pigs (N=12 for each type)according to the method set forth in “Restenosis After BalloonAngioplasty—A Practical Proliferative Model in Porcine CoronaryArteries,” by Robert S. Schwartz, et al, Circulation 82(6):2190-2200,December 1990, and “Restenosis and the Proportional Neointimal Responseto Coronary Artery Injury: Results in a Porcine Model” by Robert S.Schwartz et al, J Am Coll Cardiol; 19; 267-74 Feb. 1992 with the resultthat when compared with the controls, the dexamethasone-coated stentsreduced the amount of proliferation associated with the arterial injury.

The complete disclosures of all patents, patent applications, andpublications referenced herein are incorporated herein by reference asif individually incorporated. Various modifications and alterations ofthis invention will become apparent to those skilled in the art withoutdeparting from the scope and spirit of this invention, and it should beunderstood that this invention is not to be unduly limited toillustrative embodiments set forth herein.

1. A method for delivery of a therapeutic substance to the interior of abody lumen using a radially expandable intravascular stent, the stentbeing made by applying to the stent a mixture of a solvent, a polymerdissolved in the solvent and a therapeutic substance dispersed in thesolvent, evaporating the solvent to provide a coat of therapeuticsubstance and polymer on the stent, and repeating the applying andevaporating until a plurality of coats of therapeutic substance andpolymer are on the stent, said method for delivery comprising the stepsof: introducing the stent and the plurality of coats of therapeuticsubstance and polymer transluminally into a selected portion of the bodylumen; and radially expanding the stent and the plurality of coats oftherapeutic substance and polymer into contact with the body lumen suchthat the plurality of coats of therapeutic substance and polymer areretained on the stent, wherein the ratio of therapeutic substance topolymer in the mixture is in the range of about 10:1 to 1:100.
 2. Themethod according to claim 1, wherein the stent has a metal surface. 3.The method according to claim 1, wherein the mixture is applied to thestent by spraying.
 4. A method for delivery of a therapeutic substanceto the interior of a body lumen, comprising the steps of: introducing astent having a plurality of coats of therapeutic substance and polymeron a surface thereof transluminally into a selected portion of the bodylumen; and radially expanding the stent and the plurality of coats oftherapeutic substance and polymer into contact with the body lumen suchthat the plurality of coats of therapeutic substance and polymer areretained on the surface, wherein the stent is made by the process of:(a) providing a generally cylindrical, balloon expandable metal stentbody having a surface; (b) spraying onto the stent body a solution whichincludes a solvent, a polymer dissolved in the solvent and a therapeuticsubstance dispersed in the solvent; (c) evaporating the solvent toprovide a coat of therapeutic substance and polymer on the surface; and(d) repeating steps (b) and (c) until a plurality of coats oftherapeutic substance and polymer are on the surface, wherein the ratioof therapeutic substance to polymer in the mixture is in the range ofabout 10:1 to 1:100.